title: Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide.
abstract: OBJECTIVE
  A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations.
  
  
  METHODS
  Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated.
  
  
  RESULTS
  In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables.
  
  
  CONCLUSIONS
  Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.
authors.affiliation: Asthma and Allergy Research Group, University of Dundee, Dundee, Scotland, UK.
authors.forename: Karine L
authors.initials: KL
authors.lastname: Clearie
authors.forename: Peter A
authors.initials: PA
authors.lastname: Williamson
authors.forename: Karen
authors.initials: K
authors.lastname: Meldrum
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.forename: Lars-Goran
authors.initials: LG
authors.lastname: Carlsson
authors.forename: Marie
authors.initials: M
authors.lastname: Carlholm
authors.forename: Jan
authors.initials: J
authors.lastname: Ekelund
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lipworth
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000335:Aerosol Propellants / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019819:Budesonide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017402:Chlorofluorocarbons / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D012129:Respiratory Function Tests; D013810:Therapeutic Equivalency; D016896:Treatment Outcome
chemical_list: D000335:Aerosol Propellants; D001993:Bronchodilator Agents; D017402:Chlorofluorocarbons; D006845:Hydrocarbons, Fluorinated; D019819:Budesonide